The K+–Cl− Cotransporter KCC2 and Chloride Homeostasis: Potential Therapeutic Target in Acute Central Nervous System Injury

Abstract

The K(+)-Cl(-) cotransporter-2 (KCC2) is a well-known member of the electroneutral cation-chloride cotransporters with a restricted expression pattern to neurons. This transmembrane protein mediates the efflux of Cl(-) out of neurons and exerts a critical role in inhibitory γ-aminobutyric acidergic (GABAergic) and glycinergic neurotransmission. Moreover, KCC2 participates in the regulation of various physiological processes of neurons, including cell migration, dendritic outgrowth, spine morphology, and dendritic synaptogenesis. It is important to note that down-regulation of KCC2 is associated with the pathogenesis of multiple neurological diseases, which is of particular relevance to acute central nervous system (CNS) injury. In this review, we aim to survey the pathogenic significance of KCC2 down-regulation under the condition of acute CNS injuries. We propose that further elucidation of the molecular mechanisms regarding KCC2 down-regulation after acute CNS injuries is necessary because of potential promising avenues for prevention and treatment of acute CNS injury.

Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

“…25,28,29 REHAB seems to normalize Cl − homeostasis and improve behavioral recovery by modulating expression of Cl − transporters, 14 although we did not assess this. Future studies will assess whether therapies targeted to normalize ion concentrations (eg, bumetanide) provide benefit after ICH.…”

“…Imbalances in Cl − homeostasis can reverse the polarity of GABA signaling by altering expression of ion transporters (eg, KCC2 [potassium-chloride cotransporter] and sodium-potassium-chloride cotransporter). 28 A shift in the reversal potential of Cl − causes hyperexcitability. For example, impaired Cl − homeostasis after spinal cord injury is associated with hyperreflexia.…”

The Immune System and the Role of Inflammation in Perinatal Depression

“…Studies in animals indicate that chronic mild stress activates the NLRP3 inflammasome, showing a response to DAMPs. Interestingly, blockade of NLRP3 reverses the stress-induced increases of IL-1b in the blood and brain, abolishing the stress-induced depressive-like behavior in mice [90,91]. Furthermore, glucocorticoids arising from chronic stress or prolonged exposure to inflammatory cytokines can lead to an increased predisposition for the release of IL-1b and other cytokines [54,92,93].…”

Neuronal Transmembrane Chloride Transport Has a Time-Dependent Influence on Survival of Hippocampal Cultures to Oxygen-Glucose Deprivation

“…Thus, KCC2 mRNA and protein levels are significantly downregulated in rats after ischemia [17,18], in a process involving the endogenous brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) receptors [19][20][21]. This contributes to the disruption of Cl − extrusion, leading to its accumulation after oxygen-glucose deprivation (OGD) and a diminished GABAergic inhibition [17]. On the other hand, NKCC1 expression during ischemia remains unchanged, while its activity increases through phosphorylation of its threonine residues [22].…”

“…During the ischemic process, there are several alterations in the expression and activity of cation-chloride transporters, that lead to a higher [Cl − ] i . Thus, KCC2 mRNA and protein levels are significantly downregulated in rats after ischemia [17,18], in a process involving the endogenous brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) receptors [19][20][21]. This contributes to the disruption of Cl − extrusion, leading to its accumulation after oxygen-glucose deprivation (OGD) and a diminished GABAergic inhibition [17].…”